Increasing α₇β₁-integrin promotes muscle cell proliferation, adhesion, and resistance to apoptosis without changing gene expression

Abstract

Liu J, Burkin DJ, Kaufman SJ. Increasing ␣7␤1-integrin promotes muscle cell proliferation, adhesion, and resistance to apoptosis without changing gene expression. Am J Physiol Cell Physiol 294: C627-C640, 2008. First published November 28, 2007 doi:10.1152/ajpcell.00329.2007.-The dystrophin-glycoprotein complex maintains the integrity of skeletal muscle by associating laminin in the extracellular matrix with the actin cytoskeleton. Several human muscular dystrophies arise from defects in the components of this complex. The ␣ 7␤1-integrin also binds laminin and links the extracellular matrix with the cytoskeleton. Enhancement of ␣ 7-integrin levels alleviates pathology in mdx/utrn Ϫ/Ϫ mice, a model of Duchenne muscular dystrophy, and thus the integrin may functionally compensate for the absence of dystrophin. To test whether increasing ␣ 7-integrin levels affects transcription and cellular functions, we generated ␣ 7-integrin-inducible C2C12 cells and transgenic mice that overexpress the integrin in skeletal muscle. C2C12 myoblasts with elevated levels of integrin exhibited increased adhesion to laminin, faster proliferation when serum was limited, resistance to staurosporine-induced apoptosis, and normal differentiation. Transgenic expression of eightfold more integrin in skeletal muscle did not result in notable toxic effects in vivo. Moreover, high levels of ␣ 7-integrin in both myoblasts and in skeletal muscle did not disrupt global gene expression profiles. Thus increasing integrin levels can compensate for defects in the extracellular matrix and cytoskeleton linkage caused by compromises in the dystrophin-glycoprotein complex without triggering apparent overt negative side effects. These results support the use of integrin enhancement as a therapy for muscular dystrophy. myoblast proliferation; integrin transgenic mice; microarray CELLS CAN RECOGNIZE AND INTERACT with their environment through membrane receptors specific for different extracellular matrix proteins. The heterodimeric integrins are evolutionarily conserved receptors for matrix proteins found in all metazoans (37). In skeletal muscle, the association of the extracellular matrix with the cytoskeleton is essential for maintaining the integrity of the sarcolemma, sustaining appropriate myofiber architecture, and correctly transmitting the forces produced by muscle contractions (5, 42). The ␣ 7 ␤ 1 -integrin is part of a linkage system that maintains such transmembrane associations in skeletal muscle (10,66). It binds to laminin in the basal lamina that surrounds muscle fibers. Within muscle fibers, the integrin associates with the subsarcolemmal cytoskeleton network through focal adhesion complexes (5). The ␣ 7 ␤ 1 -integrin is distributed along the sarcolemma at costameres, and it is also concentrated at neuromuscular and myotendinous junctions (2,48). This localization suggests that the integrin has a pivotal role in maintaining these specialized structures and their functions in skeletal muscle. Congenital myopathies caused by mutations in t...

Loss of mouse cardiomyocyte talin-1 and talin-2 leads to β-1 integrin reduction, costameric instability, and dilated cardiomyopathy

“…Thus, in the KO CMs vs. controls, the localization changed, but the total amount of α7 integrin did not. Previous studies in skeletal muscle have shown that the α7-integrin subunit can be retained in the endoplasmic reticulum when there is an excess of protein (45,46). We suggest that this occurs in the Tln2KO CMs.…”

Transcriptional profile of GTP-mediated differentiation of C2C12 skeletal muscle cells

“…Integrin alpha 7 codes for a transmembrane protein of skeletal and cardiac muscle that links the cytoskeleton to the extracellular matrix. In C2C12 myoblasts, elevated levels of integrin result in increased adhesion to laminin, when serum is limiting [62]. Upregulation of integrin alpha 7 mediates cytoskeletonmembrane-extracellular matrix interactions [63].…”

Prognostic significance of c-Myc expression in soft tissue leiomyosarcoma

“…26,27 Conversely, the downregulation of ITGA7 modulates interactions between integrins and the extracellular matrix such that fibronectin binding is favored. 27 In mammary epithelial cells, fibronectin-dependent signaling has been shown to upregulate c-Myc expression through the activation of the MEK-ERK pathway.…”